About three billion people live in malaria endemic areas and approximately 300 million will develop clinical cases of the disease. Emergence of malaria parasites resistant to all available drugs, unfortunately, makes the prospects of controlling the disease by chemotherapy very difficult. Most of the current antimalarials were developed decades ago and many are derived from older drugs. Because of this dire situation for malaria therapy it is extremely important to identify new potent and selective antiplasmodial chemotypes that are structurally distinct from existing antimalarials. It is believed that scaffold of natural product (NP) origin have structural cues that enable them to interact with proteins. Thus NPs exemplify privileged structural elements that can be exploited as pre-validated starting points for novel synthetic library creation. The proposed research project seeks to identify novel antiplasmodial compounds through unbiased cell-based screen of natural product-inspired compound libraries containing structurally diverse three-dimensional scaffolds containing an increased number of sp3-hybridized carbons. These compounds belong to underexplored areas of the chemical space. We hypothesize that NP-inspired synthetic scaffolds have a very high likelihood of yielding novel antimalarial chemotypes because of their high diversity that has not been previously explored for antimalarial development. To accomplish the objective of identifying new antiplasmodial compounds and prove our hypothesis, we plan to: (a) Screen natural product-inspired a BioDesign synthetic library, and a spiroketal, polyketide, alkaloid library to identify antiplasmodial scaffolds using an unbiased cel-based growth inhibition assay; (b) Determine selectivity, stage-specific activity, and pharmacological properties for prioritization of hits. The proposed research is highly innovative and significant as it addresses an unmet need in the field- new drug leads to support global malaria elimination campaign.